Expression of PRIP, a phosphatidylinositol 4,5-bisphosphate binding protein, attenuates PI3K/AKT signaling and suppresses tumor growth in a xenograft mouse model
Year: 2021
Type: article
Abstract: Cancer is characterized by uncontrolled proliferation resulting from aberrant cell cycle progression. The activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling, a regulatory pathway for the cell cycle, stabilizes cyclin D1 in the G1 phase by inhibiting the activity of glycogen synthase kinase 3β (GSK3β) via phosphorylation. We previously reported that phospholipase C-related catalytically inactive protein (PRIP), a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] binding protein, regulates PI3K/AKT signaling by competitively inhibiting substrate recognition by PI3K. Therefore, in this study, we investigated whether PRIP is involved in cell cycle progression. PRIP silencing in MCF-7 cells, a human breast cancer cell line, demonstrated PI(3,4,5)P3 signals accumulated at the cell periphery compared to that of the control. This suggests that PRIP reduction enhances PI(3,4,5)P3-mediated signaling. Consistently, PRIP silencing in MCF-7 cells exhibited increased phosphorylation of AKT and GSK3β which resulted in cyclin D1 accumulation. In contrast, the exogenous expression of PRIP in MCF-7 cells evidenced stronger downregulation of AKT and GSK3β phosphorylation, reduced accumulation of cyclin D1, and diminished cell proliferation in comparison to control cells. Flow cytometry analysis indicated that MCF-7 cells stably expressing PRIP attenuate cell cycle progression. Importantly, tumor growth of MCF-7 cells stably expressing PRIP was considerably prevented in an in vivo xenograft mouse model. In conclusion, PRIP expression downregulates PI3K/AKT/GSK3β-mediated cell cycle progression and suppresses tumor growth. Therefore, we propose that PRIP is a new therapeutic target for anticancer therapy.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,690
Awards: Study on PRIP roles in cancer cell proliferation and migration, Development of a novel anti-inflammatory drug targeting miRNAs common to obesity and periodontitis, Development of a new treatment for obese diabetic periodontitis using anti-inflammatory miRNA-encapsulating exosomes, Novel drug discovery for dislipidemia, Studies on the effect of maternal uncarboxylated osteocalcin on the metabolic properties of next generation, Research for elucidating mechanisms of stress vulnerability as basis of brain dysfunction caused by periodontal disease, Development of a control method for depth of anesthesia and/or sedation applied to a selective dopamine receptor subtype ligand., Functional analysis of a new anti-cancer molecule that promotes anti-tumor immune responses, Roles of osteocalcin for energy metabolism, Development of a novel general anesthetic method of applying the enhancement of descending pain suppression system by stimulation of dopamine neurons of the nucleus accumbens, G8427210272
OpenAlex ID: W3138345656